Search

Objective The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn’s disease. Design In a double-blind, randomised, placebocontrolled proof-of-concept study, 59 patients with moderate to severe Crohn’s disease (Crohn’s Disease Activity Index (CDAI) $220 to #450) were assigned in a 2:1 ratio to 2310 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by Bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by $50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response. Results 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (ƒ¢CDAI (SD) .33.9 (19.7), 95% credible interval 4.9 to 72.9) that secukinumab reduces CDAI by $50 points more than placebo. Secondary area under the curve analysis (weeks 4e10) showed a significant difference (mean DCDAI.49; 95% CI (2 to 96), p.0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP$10 mg/l and/or faecal calprotectin$200 ng/ml; mean DCDAI.62; 95% CI (-1 to 125), p.0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p.0.00035 Bonferroni-corrected). Conclusions Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. INSET: Significance of this study. [ABSTRACT FROM AUTHOR]

Introduction: The precise etiology of Crohn's disease (CD) is still to be explained. Recent data suggest that CD is due to a loss of balance between pro- and anti-inflammatory agents and the overactivity of Th1 and Th17 cells. Aim of the study: Our project was aimed to investigate the Th1/Th2/Th17 serum cytokine profile in patients with CD. Material and methods: A group of 50 adults with diagnosed CD was enrolled. All the patients were classified according to the Crohn's Disease Activity Index as having an active, moderate-to-severe form of CD (CDAI ≥220). Serum samples were cytometrically tested for concentrations of IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-α and IFN-γ. Results: Statistical analysis showed significantly higher serum levels of IL-2, IL-6, IL-17A, TNF-α and IFN-γ in CD patients comparing to the control group (p<0.05). No significant differences in IL-4 and IL-10 serum levels were observed. In our study, we demonstrated the predominance of Th1 cytokine profile in the serum of moderate-to-severe CD patients. We also found higher levels of IL-17A, suggesting a possible role of recently discovered Th17 cells in the pathogenesis of CD. Conclusions: Active moderate-to-severe Crohn's disease is characterized by Th1/ Th17 serum cytokine profile. The precise role of Th17 cells, however, is still not known, and further research is needed to elucidate it and to explore the potential of new therapeutic strategies in CD patients. [ABSTRACT FROM AUTHOR]